The use of effective antiretroviral therapy (ART) to treat HIV-infected individuals has dramatically changed the clinical outcome for many patients and has led to a substantial decline in the incidence of AIDS and in AIDS-related mortality. However, it is now clear that prolonged suppression of plasma viremia by ART is not likely to eradicate HIV in most infected individuals. In addition, long-term ART may lead to drug-induced toxicities, difficulties in adhering to drug regimens, and development of drug-resistant virus. Thus, a better understanding of how the host immune system controls HIV replication is important in developing alternative immunologic strategies aimed at efficient suppression of HIV in infected individual.[unreadable] [unreadable] pDCs are important mediators of innate immunity and act mainly through secretion of interferon (IFN)-a. Previous studies have found that these cells can suppress HIV in vitro. Additionally, pDCs have been shown to be severely reduced in the peripheral blood of HIV-infected individuals. Over the past year, we sought to determine the ability of pDCs to directly suppress viral replication ex vivo and to delineate the potential mechanisms whereby pDCs are depleted in HIV-infected individuals. We demonstrated that activated pDCs strongly suppress HIV replication in autologous CD4+ T cells via a mechanism involving IFN-a as well as other antiviral factors. Of note, unstimulated pDCs from infected individuals who maintained low levels of plasma viremia without antiretroviral therapy were able to suppress HIV ex vivo via mechanisms requiring cell-to-cell contact. Our data also demonstrated that death of pDCs by apoptosis and necrosis is induced by fusion of HIV with pDCs. Taken together, our data suggested that pDCs play an important role in the control of HIV replication and that high levels of viral replication in vivo are associated with pDC cell death via apoptosis and necrosis. Elucidation of the mechanisms by which pDCs suppress HIV replication in vivo may have clinically relevant implications for future therapeutic strategies.